The present invention relates to ultrasound systems for delivering therapeutic ultrasound energy to a target region of a patient""s body.
A current standard technique for the delivery of drugs or other substances into the human body is needle injection, in particular, intramuscular injection (IM). A bolus containing the substance is typically injected into muscle where it diffuses through the interstitial fluid or pools between muscle layers and thence diffuses through the same or more distant interstitial fluid. This diffusion might spread over a length of five or more centimeters parallel to the muscle fibers and over a width of perhaps one or two centimeters normal to the fibers. Over a period of time, typically on the order of 10 to 100 minutes, the vascular system of the body takes over and flushes the substance out of the interstitial fluid and into the capillaries. From there, the cardiovascular system widely distributes the substance into the rest of the patient""s body.
Newly developed drugs often have application only to specific organs or sections of organs. As such, systemic distribution of the drug throughout the remainder of the body can: (1) dilute very expensive drugs, weakening their effects, (2) generate an effect systemically instead of locally, and (3) widely distribute a drug which may be toxic to other organs in the body. Furthermore, some of the newly developed drugs include DNA in various forms, such DNA being degraded very rapidly by natural mechanisms in the body if delivered systemically, thus preventing a full dose from reaching the designated organ.
In vitro experiments by H. J. Kim, et. al. (Human Gene Therapy, 7, 1339-1346, Jul. 10, 1996) and in vivo experiments by S. Bao, et. al. (Cancer Research 58, 219-221, Jan. 15, 1998) have demonstrated enhanced transfection of DNA into human cell lines by supplementary application of lower frequency ultrasound. While the exact biological response to DNA in conjunction with ultrasound remains unclear, it is accepted that mechanical mechanisms are responsible for the temporary permeabilization of cell membranes and possibly cell nuclear membranes.
Accordingly, it would be desirable to provide ultrasonic devices, kits, and methods for delivering such site-specific drugs in a manner which enhances absorption and/or transfection specifically into the cells within the injection diffusion zone, specifically around the site of their delivery into a target region of a patient""s body. Substances thus absorbed directly into the cells or further into the nucleus of the cells have maximum potency at or around the injection site and reduced diffusion throughout the remainder of the body. Furthermore, it would be desirable for the enhancement mechanism to be mechanical in origin, as compared to thermal in origin. Mechanical methods may function to temporally permeabilize cellular membranes as compared to thermal mechanisms which may give rise to tissue inflammation.
By way of example, it has been demonstrated that injection of plasmid DNA which expresses vascular endothelial growth factor (VEGF) promotes growth of collateral vessels in ischemic tissue. Exposure of the same muscle tissue to ultrasound in conjunction with these injections improves the cellular uptake and/or transfection and manifestation of the DNA. The current problem is that these DNA injections are typically directed to specific target muscles. The injection bolus typically follows the muscle fibers, spreading as described above. Furthermore, it has been demonstrated that natural bodily defense mechanisms degrade the potency of DNA, typically by as much as fifty percent in the matter of a few minutes.
Ultrasonic systems which might be ineffectively used for enhanced transfection of DNA or for the cellular uptake of other drugs by various biological cells do exist. Unfortunately, either these systems produce very narrow ultrasound beams due to operation in the focal zone or far field (Fraunhofer zone) or they produce broad irregular fields due to operation in the near field (Fresnel zone). In the first case, the narrow beams cannot deliver a satisfactory dose of ultrasound to the volume of tissue in a time frame short compared to the natural biological destruction of the DNA. In the second case, the irregular fields are characterized by large differences in acoustic intensity both in the lateral direction (parallel to the transducer surface) and in the axial direction (normal to the transducer surface), such differences leading to unpredictable amounts of ultrasound dose.
Systems which operate in the focal zone and far field (Fraunhofer zone) include medical diagnostic ultrasound imaging and Doppler systems. These feature very tight acoustic scanning beams for the purpose of achieving the highest possible lateral resolution. Furthermore, ultrasound tissue exposure in scanning beams is held to the frame rate of the system display, typically 30 Hz. Maximum signal strengths are limited by industry and FDA guidance protocols. These systems furthermore operate at higher frequencies, in the range where longer bursts of ultrasound or continuous ultrasound exposure would create a heating effect due to absorption of the ultrasound energy in the tissues. These systems would be incapable of delivering the mechanical ultrasound effects to achieve acceptable therapeutic effects.
Additional systems which operate with highly focused beams include low frequency lithotripters and high frequency thermal ablation systems. Lithotripters feature short bursts of high intensity ultrasound with a very low burst repetition rate. They cannot provide broad tissue coverage with a high duty cycle. Ablation systems, typically identified as high intensity focused ultrasound (HIFU) systems, function to create thermal lesions in living tissue. While their acoustic beams might be swept through tissue for wide area coverage, their high frequency operation fails to produce mechanical effects in tissue.
Systems which operate in the near field (Fresnel zone) include ultrasound divices for physical therapy applications. These systems typically feature large surface area contact transducers which are intended to develop deep heat in damaged tissues, as compared to mechanical (non thermal) effects.
Currently, no systems exist for distributing a uniform wide beam of ultrasound for a mechanical (substantially non thermal) effect over a large volume of tissue, in a short period of time, so as to promote uniform cellular uptake of drugs and/or to uniformly enhance transfection of DNA over a large tissue volume. Such transcutaneous uniform acoustic intensity would need to be sufficiently powerful so as to cause acceptable cellular absorption and/or transfection yet sufficiently weak to prevent cell lysis or DNA fractionation. More specifically, no system exists for applying a uniform dose of therapeutic ultrasound, in a timely manner, over an area of a spreading injectate bolus.
The present invention provides systems, methods and kits for delivering a uniform field of ultrasound energy over a wide target region of a patient""s body. The present invention offers the advantages of enhancing cellular absorption and/or transfection of therapeutic substances delivered by injection into a patient""s body. In another aspect, the present invention is also useful for the treatment of vascular structures at risk from intimal hyperplasia.
Co-pending applications Ser. No. 09/364,616, Ser. No. 09/255,290, and Ser. No. 09/126,011, describe systems for ultrasound enhancement of drug injection.
The present invention provides a variety of wide beam ultrasound delivery systems which have the advantage of delivering therapeutic ultrasound energy over a large tissue volume such that, in preferred aspects, ultrasound energy can be uniformly distributed over the region in which a therapeutic substance has been injected intramuscularly, in a short time frame as compared to the lifetime of the substance at the site of interest. An advantage of the present invention is that by applying a uniform field of ultrasound energy over a large tissue volume, cellular uptake of injected substances such as therapeutic DNA can be substantially enhanced over the entire region in which the injected DNA spreads without inflicting tissue damage or degrading the injectate. Another advantage of the present invention is that by applying a uniform field of ultrasound energy over a long length of vascular structure, a healing response might be invoked to blunt excessive growth of intimal hyperplasia without adjacent tissue damage.
An advantage of the present invention is that it provides systems for both delivering wide ultrasound beams and for scanning ultrasound beams. As such, the present invention is particularly well adapted to operate under both conditions in which time constraints are present and conditions under which time constraints are not present, as follows.
If time constraints exist, therapeutic applications requiring continuous wave (CW) exposure by ultrasound will require devices which have fields of view larger than the insonication area of interest. If there is no time limit such as that limit imposed by the natural degradation of DNA within the body, devices with smaller fields of view may be swept or stepped over the insonication area of interest.
Again, if time constraints exist, therapeutic applications which operate with pulse wave (PW) exposure by ultrasound may also require devices which have fields of view larger than the insonication area of interest if the ultrasound beam cannot be shifted away from a first sonication site during the OFF time to a second (or third, or fourth, . . . ) sonication site for the ON time of that second (or third, or fourth, . . . ) site. For applications with very small duty cycles, where duty cycle is defined as the ratio of the ON time divided by the ON and OFF time, the ultrasound beam may be swept across a multitude of alternative sites, the net effect being a similar amount of ultrasound exposure (uniform exposure) to all points within the subject area of interest.
In preferred aspects, the present wide beam ultrasound delivery system comprises a housing having an opening at its distal end with an ultrasound transducer suspended within the housing. The ultrasound transducer is positioned in contact with an acoustic couplant material which substantially fills the housing. In preferred aspects, the acoustic couplant material is a fluid such as water, water with additives such as wetting agents and/or anti biological agents (to prevent build up of bacteria or fungus), or oils.
A flexible skin-contact window, which may be made from any of several variations of silicone rubber, polyethylene, polypropylene, nylons, urethanes and the like, is disposed across the opening at the distal end of the housing. The skin-contact window is preferably positioned adjacent to the patient""s skin with possibly an ultrasonic coupling gel between the window and skin such that therapeutic ultrasound energy can be conducted from the ultrasound transducer along through the fluid-filled housing and then through the skin-contact window and into the patient.
In preferred aspects of the present invention, the housing of the ultrasound delivery system is designed to assure good coupling of ultrasonic energy to the external configuration of the patient. Additionally the housing preferably contains adequate ultrasonic absorbing materials such that ultrasonic energy does not propagate to the external surface of the housing thus sonicating the operator of the equipment. Furthermore, the housing preferably is designed such that it does not interfere with the ultrasonic beam in the form of unintended ultrasonic beam stops.
In various aspects, the piezoelectric element of the ultrasound transducer is generally planar and may either be rectangular, circular, or annular in shape. In particular embodiments, the transducer may comprise a plurality of annular-shaped piezoelectric elements disposed concentrically, one within another. Alternatively, the transducer may comprise piezoelectric elements which are generally cylindrical in shape. In further embodiments, the transducer may comprise single or multiple element three dimensional piezoelectric shapes. Yet further, the transducer may comprise a two-dimensional array of individual flat-plate piezoelectric elements. The transducer elements of the present invention preferably have a large surface area ranging, in preferred aspects, from typically 0.5 cm2 to 1000 cm2.
It is understood that the shape of the piezoelectric element of the transducer in association with any and all focussing elements will effect the shape of the ultrasonic footprint in tissue, defined as the area of therapeutically effective ultrasound. Some applications of the present systems may preferably use circular footprints while others may preferably use rectangular shapes. By way of example, an unfocussed rectangular transducer might produce a rectangular footprint with the long axis of the transducer being orthogonal to the long axis of the footprint.
In preferred aspects, the present invention also comprises various systems for directing the ultrasound energy through the fluid filled housing to targeted depths in the patient""s body. Such systems may optionally comprise curving the piezoelectric ceramic to shape the beam width. Alternately, lens structures may be attached to the front emission surface of the piezoelectric ceramic to effect the same. Further, reflective surfaces may be installed in the housing so as to achieve the same. And yet furthermore, refractive acoustic lenses may be placed in the acoustic beam in the fluid couplant medium to shape the beam width.
In preferred aspects, the back surface of the piezoelectric ceramic is covered with air to assure the emission of all acoustic energy out the front surface of the same. Consequently thermal dissipation corresponding energy backward radiated in the device will be substantially reduced and maximal efficiency achieved. Alternately, the back surface of the ceramic may instead be covered with low impedance lightly attenuating materials to provide some level of structural strength to the device. Preferably, the edges of the piezoelectric ceramic are mounted within the housing so as to minimize acoustic coupling to the housing.
In alternative aspects of the invention, first and second mounting systems are provided for connecting the transducer to the interior of the housing such that the transducer can be articulated for controllable back-and-forth scanning movement of a beam of ultrasound energy. Preferably, by moving the transducer back-and-forth in two perpendicular directions, a narrower beam of ultrasound energy can be raster scanned across the desired volume of tissue in the patient and over time achieve uniform illumination of subject tissues.
The present invention is particularly well suited for (although not constrained to) use in conjunction with intramuscular injections of therapeutic substances such as DNA. In such aspects, the present wide aperture ultrasound delivery system can be used either before, concurrently with, immediately after, or substantially after the injection of a therapeutic substance into the patient. As defined herein, application of ultrasound xe2x80x9csubstantially afterxe2x80x9d injection comprises application of ultrasound in the period of time before which the injected DNA has been substantially degraded. Typically, such a time period will be on the order of 15 to 60 mins., but is not so limited and may vary from one application to another.
As such, the present invention is ideally suited for enhancing cellular absorption of a drug or any other substance into a local target region of a patient""s body, thereby avoiding the undesirable effects of the substance being widely dispersed throughout the patient""s body by the patient""s cardiovascular system.
For example, specific applications of the present invention include the application of sonicated VEGF therapy for the treatment of ischemic tissues as described above. Further applications include the treatment of patients suffering from diseases as a result of specific protein deficiencies. Specifically, such patients may be helped by the injection of specific DNA plasmids to stimulate cells to secrete these proteins, such as EPO for patients with impaired production of red blood cells, Factor VIII or Factor IX for hemophiliac patients, or angiostatin or endostatin for cancer patients.
The present system""s advantageous applications of a uniform wide beam ultrasound exposure are not limited to those in conjunction with substance injection. For example, the present invention is also particularly well suited for use in the prevention of intimal hyperplasia in conjunction either before, concurrently with, immediately after, or substantially after vascular intervention or surgery. As such, a further advantageous application of the present invention is its ability to distribute a uniform wide beam of ultrasound for a mechanical (non thermal) effect to evoke a vascular healing response along an extended portion of artery or vein.
It has been demonstrated that vascular tissues at risk of intimal hyperplasia, such as coronary or peripheral arteries following vascular intervention or veins and arteries following graft insertion or the creation of a fistula, experience a reduced hyperplasia burden if treated with ultrasound immediately following injury. In the case of vascular intervention with devices such as angioplasty balloons, arthrectomy catheters, or stents, the extent of vascular injury might range from a few millimeters in length to several centimeters or more in length.
Co-pending applications Ser. No. 09/223,230, and Ser. No. 09/345,661, describe catheter based systems for delivering a field of ultrasound to a region of tissue.
In addition to encompassing systems for delivering a wide field of uniform ultrasound to the surface of a patient""s skin, the present invention also encompasses wide beam aperture systems for delivering a wide field of uniform ultrasound to a region of tissue to inhibit intimal hyperplasia in the vascular system.
In accordance with the present invention, patients receive a wide field of uniform ultrasound exposure from external sources either during the initial vascular intervention or some period thereafter. Such transcutaneous uniform acoustic intensity is preferably of a sufficient power so as to excite the healing response yet is not excessively strong to evoke an inflammatory response or to lyse blood or tissue cells.
The present invention is not limited as to the nature of the cells which compose the target site. Such cells may be muscle or organ cells receiving transcutaneous, intraoperative, or percutaneous injection. Such cells may include vascular cells.